Department of Pathology and Cell Biology, Columbia University College of Physicians and Surgeons, New York, New York 10032, USA.
J Neurosci. 2011 Mar 2;31(9):3186-96. doi: 10.1523/JNEUROSCI.4011-10.2011.
The generation, differentiation, and migration of newborn neurons are critical features of normal brain development that are subject to both extracellular and intracellular regulation. However, the means of such control are only partially understood. Here, we show that expression of RTP801/REDD1, an inhibitor of mTOR (mammalian target of rapamycin) activation, is regulated during neuronal differentiation and that RTP801 functions to influence the timing of both neurogenesis and neuron migration. RTP801 levels are high in embryonic cortical neuroprogenitors, diminished in newborn neurons, and low in mature neurons. Knockdown of RTP801 in vitro and in vivo accelerates cell cycle exit by neuroprogenitors and their differentiation into neurons. It also disrupts migration of rat newborn neurons to the cortical plate and results in the ectopic localization of mature neurons. On the other hand, RTP801 overexpression delays neuronal differentiation. These findings suggest that endogenous RTP801 plays an essential role in temporal control of cortical development and in cortical patterning.
新生神经元的产生、分化和迁移是正常大脑发育的关键特征，受到细胞外和细胞内调节的影响。然而，这种控制的手段只是部分被理解。在这里，我们表明，RTP801/REDD1 的表达（mTOR 激活的抑制剂）在神经元分化过程中受到调节，并且 RTP801 发挥作用以影响神经发生和神经元迁移的时间。RTP801 的水平在胚胎皮质神经祖细胞中较高，在新生神经元中降低，在成熟神经元中较低。体外和体内敲低 RTP801 可加速神经祖细胞的细胞周期退出及其向神经元的分化。它还扰乱了新生大鼠神经元向皮质板的迁移，并导致成熟神经元的异位定位。另一方面，RTP801 的过表达会延迟神经元的分化。这些发现表明，内源性 RTP801 在皮质发育的时间控制和皮质模式形成中发挥着重要作用。
